Immunological approaches have failed in the treatment of autoimmune diseases thus far. For example, in the long-term treatment of autoimmune type 1 diabetes (T1D). Despite considerable effort to halt or delay the destruction of beta-cells in T1D, success remains elusive. Historically, approaches aiming to treat T1D have made a negligible number of subjects insulin-independent. The Diabetes Control and Complications Trial (DCCT) have demonstrated that improving glucose control and preserving β-cell function in individuals with T1D lowered the incidence of diabetic complications.
Stem cells have been used for autoimmune diabetes treatment. Mesenchymal stem cells (MSCs) are fibroblast-like non-hematopoietic progenitor cells with the capacity for adipogenic, chondrogenic, and osteogenic differentiation. MSCs, because of their immunomodulatory properties and their potential to differentiate into insulin-producing cells, represent a viable therapeutic option for autoimmune diabetes A study showed short-term reversal of diabetes in 88% of BALB/c-MSC-treated hyperglycemic NOD mice. However, NOD mice treated with NOD-MSCs remained hyperglycemic. Further reports indicated that treatment with congenic NOR-MSCs resulted in a more pronounced and prolonged reversal of hyperglycemia in treated NOD mice (88% and 62% short-term and long-term reversal respectively), suggesting the potential use of haplo-identical MSCs in autoimmune diabetes. Based on this data, a clinical trial was initiated in the US by the JDRF and by the Osiris Corporation, but interim unpublished results at 1-year of follow-up were disappointing. Furthermore, safety concerns primarily related to potential oncogenic transformation of MSCs may limit their use in the clinical setting. (Moufida Ben Nasr et al., (2015), “The rise, fall, and resurgence of immunotherapy in type 1 diabetes. Pharmacological Research”, 98:31-38).
Hematopoietic stem cells (HSCs) transplantation has been reported to yield promising results in long term treatment of TID. Towever, accumulating clinical data show limited success for long-term insulin independence and for a limited population with the condition. HSCs may provide treatment solutions because HSCs are endowed with immunoregulatory properties and can induce central and peripheral immunological tolerance per se. In 2003, Voltarelli et al. 2007 (JAMA, 297:1568-76) initiated a phase I/II study in (T1D), to evaluate the safety and efficacy of autologous HSC transplantation (AHSCT) using a combined regimen of thymoglobulin plus cyclophosphamide. The latest analysis reported 20 out of 23 of the treated patients with a mean follow-up of 30 months, insulin-free for more than 1 year. However, in the aforementioned studies, it is difficult to distinguish between the effects of concomitant immunosuppressants and the mechanisms of HSC-mediated immunomodulation.
A report from a multicenter analysis on 65 newly-diagnosed T1D individuals treated with AHSCT using a similar protocol to that previously reported showed that insulin independence in nearly 60% of treated subjects was achieved. However, several adverse events have been recorded suggesting this as a therapy for selected T1D individuals only.
Moreover, the AHSCT protocols used in these studies were designed for adults and not for pediatric subjects with T1D, and thus AHSCT can be only considered for a well-defined group of individuals that may benefit from this treatment.
HSCs are endowed with immunoregulatory properties. Preclinical studies demonstrated that T cell-depleted bone marrow-resident CD34+ stem cells overcome MHC barriers in sublethally irradiated mice and that murine HSCs may delete effector cells. This effect can be reverted by the addition of a caspase inhibitor, suggesting a deletion-based mechanism. With respect to human HSCs, the human CD34+ population have been shown to be endowed with potent veto activity and neutralized precursors of cytotoxic T lymphocytes (CTLs) directed against their antigens.
Based on that principle, research focused on finding additional immunological strategies to prevent β-cell loss in subjects with a newly diagnosed T1D have been initiated. Since then, the search for feasible and safe immunological approaches in order to re-establish tolerance toward islet autoantigens (and preserve β-cell function) is ongoing.